article · Journal of Medicinal Chemistry
Malaria continues to pose a significant burden on populations in endemic areas and requires innovative treatment options. Here, we report the synthesis and preclinical evaluation of the novel 3-hydroxypropanamidine (HPA) <b>2 (TKK130)</b>, which shows excellent antiplasmodial <i>in vitro</i> activity against drug-sensitive and -resistant <i>Plasmodium falciparum</i> strains. Moreover, in various human cell lines, the compound shows no cytotoxicity and excellent parasite selectivity. The compound inhibits synthetic hemozoin (β-hematin) formation, with IC<sub>50</sub> values lower than chloroquine (CQ), and its <i>in vitro</i> rate of activity is comparable with the fast-acting antimalarial drug dihydroartemisinin. Furthermore, selection studies reveal a very low propensity for resistance development. Based on initial <i>in vivo</i> pharmacokinetic snapshot data, <b>2 (TKK130)</b> has a long-lasting, linear pharmacokinetic profile. <i>In vivo</i>, this novel HPA exhibits curative activity in the <i>Plasmodium berghei</i>mouse model and potent activity in the<i>P. falciparum</i> SCID mouse model after oral administration.
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DOI: 10.1021/acs.jmedchem.4c01465
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